由非核酸激动剂诱导的STING明显的寡合组合
Anant Gharpure1, Ariana Sulpizio2, Johannes R Loeffler1
1Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA, USA.
Nature communications
|April 11, 2025
概括
研究人员使用冷EM探索了STING蛋白激活如何在封闭和开放的形状之间有所不同. 开放形状激动剂显示出独特的STING四级结构和更慢的激活,这表明治疗性STING激动剂开发的新型调节机制.
科学领域:
- 免疫学 免疫学 免疫学
- 结构生物学 结构生物学
- 分子生物学分子生物学
背景情况:
- STING (干扰素基因刺激器) 对于天生的免疫力至关重要,对病原体和基因组不稳定性作出反应.
- 激活STING依赖于循环二核酸 (CDN) 二次信使,这些信使在封闭或开放的构造中稳定其联结域 (LBD).
- 虽然封闭形状已得到充分研究,但开放形状诱导连接体对STING激活的结构基础尚不清楚.
研究的目的:
- 通过使用冷电子显微镜 (cryo-EM) 调查闭合与开放的诱导构造合成激素激活STING的结构差异.
- 阐明由不同的CDN类引起的STING的构造变化和寡合组合.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 来确定与封闭和开放的构造诱导激素结合的STING的结构.
- 进行了功能性测试,以评估这些不同类型的连接体激活STING的动力学.
主要成果:
- 无论是封闭的还是开放的构造诱导激素都诱导了STING的特征性180°旋转.
- 一个开放的LBD诱导激动剂,diABZI-3,独特地形成了一个四级结构,与apo-STING自抑制状态不同.
- 诱导开放形状的体表现出较慢的激活率,并建议一种涉及头对头相互作用和受限制的寡合体形成的调节机制.
结论:
- 通过开放的构造诱导连接体激活STING,涉及到独特的结构重组和调节机制.
- 这些发现表明不同类型的STING激动剂具有不同的治疗潜力.
- 了解这些差异对于优化用于特定治疗应用的STING激动剂选择至关重要.
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